先天性白内障相关基因热休克转录因子4非同义单核苷酸多态性高危致病表型的预测研究  

High-risk pathogenic phenotype predictions of non-synonymous single nucleotide polymorphisms in human heat shock transcription factor 4 gene associated with congenital cataract

作　　者：禹晓童 王震宇 黄琛[1,2] 吕会斌[2] 张明洲[2] 李学民[2] 敖明昕[2] Yu Xiaotong;Wang Zhengyu;Huang Chen;Lyn Huibin;Zhang Mingzhou;Li Xuemin(Medical Research Center, Peking University Third Hospital, Beijing 100191, China;Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China)

机构地区：[1]北京大学第三医院中心实验室,100191 [2]北京大学第三医院眼科,100191

出　　处：《中华眼科医学杂志（电子版）》2019年第2期96-104,共9页Chinese Journal of Ophthalmologic Medicine(Electronic Edition)

基　　金：国家科技重大专项基金(2018ZX10101004);北京大学第三医院种子基金(Y84496-01)

摘　　要：目的系统整合、收集单核苷酸多态性数据库和文献中热休克转录因子4(HSF4)基因非同义单核苷酸多态性(nsSNP)的信息,筛选具有高危致病的nsSNP位点。方法从单核苷酸多态性数据库、临床变异数据库、人类基因突变数据库、疾病基因网络数据库和已发表文献中,收集整理HSF4基因的nsSNP数据。利用6款突变预测软件,进行致病性预测分析,筛选高危致病nsSNP位点。应用I-变异2.0在线软件、突变所致蛋白质稳定性改变预测软件和非同义突变对蛋白质稳定性的影响软件比较氨基酸替换对蛋白质稳定性的影响,利用氨基酸保守性评估在线软件、带对齐的自优化预测在线软件和蛋白释意软件对nsSNP位点中氨基酸进化保守性、理化性质和突变前后的蛋白结构改变进行预测分析。结果通过以上数据库检索以及基因突变致病性预测软件分析,共获得31个HSF4b(HSF4基因选择性剪切形成的一种亚型)高危致病nsSNP位点。其中,11个nsSNP位点已在文献中报道,并指出与先天性白内障相关;20个nsSNP位点为本研究预测的高危致病性位点。高危致病nsSNP位点可导致25个野生型氨基酸位点被31个突变型氨基酸替换,替换的突变型氨基酸中预测有25个可能导致蛋白质稳定性下降。除了39位色氨酸外,其余24个野生型氨基酸均为高度进化保守性位点。20个位于热休克转录因子脱氧核糖核酸结合域,5个位于疏水重复序列,而成为高危致病nsSNP位点。本研究预测发现这些高危致病性位点氨基酸突变后均可导致氨基酸和蛋白质的理化性质改变,导致蛋白质二级和三级结构改变、结构域与其他分子之间相互作用的改变,进而影响蛋白功能。结论本研究预测筛选获得的31个HSF4b基因高危致病nsSNP位点,其中20个为首次报道。推测这些高危致病nsSNP位点可能是参与先天性白内障发病的重要位点,将为临床及理论研究提供�Objective The aim of this study was to systematically integrate and collect non-synonymous single nucleotide polymorphism (nsSNP) information of heat shock transcription factor 4 (HSF4) gene in single nucleotide polymorphism database and literature, and screen nsSNP loci with high risk of pathogenicity. Methods The nsSNP data of HSF4 gene were collected from dbSNP database, ClinVar database, HGMD database, DisGeNET database and published literature. The pathogenicity was predicted and analyzed by 6 software tools including Mutpred2, PANTHER-PSEP, PhD-SNP, PolyPhen 2.0, PROVEAN and SIFT. The high-risk pathogenic nsSNP was screened. I-Mutant 2.0, MUpro and INPS online software tools were used to compare the effects of amino acid substitution on protein stability. ConSurf, The Self-Optimized Prediction Method With Alignment (SOPMA) and Have (y)Our Protein Explained (HOPE) online software tools were used to predict the conservativeness of amino acid evolution, physicochemical properties and changes of protein structure before and after mutation. Results 31 HSF4b high-risk pathogenic nsSNPs were obtained by searching the mentioned databases and analyzing the results of genetic mutation pathogenicity prediction software tools. Among them, 11 nsSNPs were reported to be associated with congenital cataract and 20 were newly predicted high-risk pathogenic nsSNPs. High-risk pathogenic nsSNPs could cause 25 wild-type amino acids to be replaced by 31 mutant amino acids, and 25 mutant amino acids could be predicted to lead to decline the stability of protein. The other 24 wild-type amino acids were highly evolutionary conservative sites except 39 tryptophan. Twenty sites were located in the heat shock transcription factor DNA binding domain and five in the hydrophobic repeat sequence HR-A/B and became high-risk pathogenic nsSNPs. It is predicted that the mutation of amino acids in these high-risk pathogenic sites could cause changes in the physical and chemical properties of amino acids and proteins, resulting in changes in se

关 键 词：先天性白内障 热休克转录因子4 非同义单核苷酸多态性 致病性预测 生物信息学 

分 类 号：R776.1[医药卫生—眼科]